The long-term objectives of this proposal are to determine how commercially used spermicides, progestin-containing contraceptives and factors present in semen can increase the chances of Human Immunodeficiency Virus (HIV) infection. HIV-associated pathologies, including Acquired Immunodeficiency Syndrome (AIDS), continue to be a global pandemic as of 2011. Women in high-risk areas are infected primarily through heterosexual intercourse. Since it can be difficult culturally for certain women to negotiate the use of condoms and other forms of birth control, HIV infection continues to be an unresolved health issue for women all over the world. Recently, it was shown that the use of certain contraceptives, including spermicides that contain nonoxynol-9 (N9), as well as progestin-based contraceptives (e.g. Depo-Provera and the levonorgestrel intrauterine system) increase the HIV infection rate. Furthermore, since heterosexual infection of women by HIV is driven by infected semen, studies have also shown that factors present in semen can enhance HIV infection. Thus, the hypothesis of this proposal is that exposure to certain spermicides, progestin-based contraceptives and semen factors increase endometrial inflammation to create a pro-infectious HIV environment. The specific aims for this hypothesis will be to define and measure potential endometrial inflammatory pathways when exposed to these compounds. To address these aims, a combination of well-validated in vitro endometrial cell models will be used to elucidate pro-inflammatory pathways up-regulated by exposure to these molecules. Moreover, in vivo clinical studies will be used to validate in vitro observations. The National Institute of Health (NIH) Endometrial Tissue and DNA bank will provide the adequate human samples needed to fulfill the goals of each aim. The collaborating labs at The Gladstone Institute for Virology will provide the necessary support for subsequent studies that can investigate if a pro-inflammatory endometrial environment enhances viral activity, using active HIV infectivity assays. Thus, we will provide in vitro, in vivo and infectivity data to address the goals of each specific aim. The achievement of these goals can greatly contribute to the field of reproductive biology, immunology and virology, and provide clues as to how HIV infection, propagation and systemic spread occur in the upper female reproductive tract. To this end, updated screening tools can be developed for new pharmaceuticals and new drug development strategies can be developed. Together, this proposal will directly address the mission of the NIH by providing fundamental knowledge about the nature and behavior of living systems and applying that knowledge to enhance health, lengthen life and reduce the burdens of illness and disability. PUBLIC HEALTH RELEVANCE: The goals proposed by this fellowship grant directly address an important public health concern: The susceptibility of women using certain contraceptive products to heterosexual HIV infection. The achievement of these goals can greatly contribute to the field of reproductive biology and overall reproductive health.